Speaker 1: Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on AACE.com/podcasts. And now, let's meet the endocrine experts who will be talking with us today.

Sina Jasim, MD, MPH: Hi, and welcome to AACE Podcasts. I'm Dr. Sina Jasim, the editor-in-chief of AACE Clinical Case Report Journal and associate professor at Washington University in St. Louis. Today, I have the pleasure of hosting Dr. Janet McGill to discuss their contribution to our AACE July/August ACCR, our AACE Clinical Case Report issue, which was actually devoted to diabetes cases in association with the AACE Diabetes Guidelines and Algorithm, published by AACE earlier this year. Dr. McGill contributed very interesting cases to this issue as well as she wrote the editorial for that ACCR diabetes issue. Dr. McGill is a professor of medicine at Washington University School of Medicine in St. Louis, and an expert in the field of diabetes. Dr. McGill, thank you for joining us today.

Janet B. McGill, MD, MA, FACE, FACP: Thank you, Sina. It's a pleasure to be here.

Sina Jasim, MD, MPH: Dr. McGill, please tell us a little bit about yourself and your work.

Janet B. McGill, MD, MA, FACE, FACP: So I have had quite a career in clinical endocrinology, beginning with the diabetes controlling complications trial, the Captopril diabetic nephropathy study, and then many, many other clinical trials, but also other interests. And most recently, I am a sub-investigator on the RADIANT study that is looking to identify new genetic causes of diabetes. So identifying a genetic cause of diabetes is a relatively new interest in the last five or 10 years, and certainly has opened all of our eyes, different types of diabetes.

Sina Jasim, MD, MPH: Indeed. And that's why we're having you here today, Dr. McGill. Thank you. You shared two cases. You and your teams contributed to the issue of ACCR diabetes issue that focused mostly on diabetes care, and those cases represented a diagnostic dilemma or conundrum, as illustrated by the cases of monogenic diabetes that were initially diagnosed as either Type 1 or Type 2 diabetes. So we are discussing today two cases, and I will touch base first on the first case published in that issue, MODY 5 and Serous Ovarian Carcinoma in 17q12 Recurrent Deletion Syndrome. This particular case presented a case of a young woman whose monogenic diabetes was diagnosed after pathogenic mutation was found, and it did touch base on the disease's association reported between the MODY 5 and urogenital abnormalities. So could you tell us a little bit about this case and the highlight of this case, and the take home points specifically to this interesting case?

Janet B. McGill, MD, MA, FACE, FACP: Sure. So this is a case of a young woman who came to our attention at age 25. She had been diagnosed with diabetes at age 12, and there was a consideration all along that she not have typical Type 1 or Type 2 diabetes. She was normal weight, she had short stature, she required insulin but was not completely insulin deficient. So she was seen by pediatrics, lost to follow up for a little bit, and re-presented with abdominal swelling. The abdominal swelling was found to be a low grade serous cancer of the ovary. So it was actually genetics done on the cancer, on the ovarian neoplasm, that showed the defect, which turns out she is a monogenic 17q12 recurrent deletion syndrome. So in the workup for the cancer, of course imaging was done. She was found to have a bicornate uterus, she had somewhat cystic kidneys, and she had a partial pancreatic atrophy called pancreatic hypoplasia, accounted for her insulin deficient diabetes that was not classic Type 1.

So very interesting presentation of this HNF1 beta, which is also known as MODY 5, diagnosed in a young woman with, at this point, multiple, multiple problems. The question about this case, we know that MODY five can be associated, or is typically associated, with renal cysts. It's sometimes called RCAD, R-C-A-D, renal cysts and diabetes. The other acronym that's used for cases like this are CAKUT, congenital abnormalities of the kidney and urinary tract. Of those with KACUT, or congenital abnormalities of kidney and urinary tract, 30% have an HNF1 beta mutation.

What's interesting about these is, in about half the cases, diabetes is diagnosed before the kidney problem. In the other half of the cases, diabetes is diagnosed after the kidney problem and can be diagnosed well into adulthood. So what's important about HNF1 beta, what's very, very important, is not only is their diabetes atypical, meaning that it's insulin deficient without being completely... There's no absence of insulin. So they typically require insulin, they have renal cysts, and most progress to end stage kidney disease, though not all of them. And there is an increased risk of certain types of cancers. Ovarian is one. Clear cell renal cancer is another. Endometrioid cancers are others. So these patients not only need an accurate genetic diagnosis, but they need ongoing surveillance of their urogenital tract. In some cases, liver cysts can occur. They need ongoing follow-up for the other manifestations of their syndrome.

Sina Jasim, MD, MPH: This is fascinating. And this disease association that's reported suggests that medical providers should periodically evaluate for ovarian cancer, gut, or urogenital abnormalities in patients with MODY5, and it's probably vice versa.

Dr. McGill, the second case was also about maturity onset diabetes of the young. This case titled ABCC8-related Monogenic Diabetes presented like Type 1 diabetes in an adolescent. And this is a case of Type 1 diabetes that was diagnosed during early adolescence, and the patient was treated with insulin therapy for almost 17 years before she was finally correctly diagnosed. Can you tell us more about this case, and the highlight of that particular case, and the teaching point or taking home points of this fascinating case?

Janet B. McGill, MD, MA, FACE, FACP: Yeah, absolutely. So this is a really interesting case. The presentation was classic for Type 1 diabetes. The blood sugar was over 500. A1C was 14%, indicating that the patient had their diabetes for a period of time, which is very, very typical of Type 1 diabetes, a high A1C, high glucose. However, the patient was not in DKA and did not have DKA after that. She was noted to require relatively lower doses of insulin, though that's not always the case. She required 0.3 units per kilo, using an insulin pump. She was antibody negative. That was tested several times. Patient does not have antibodies. C-peptide was positive but low. It was 0.3 on at least one occasion.

She enrolled in TrialNet. TrialNet also found her to be antibody negative. And then the TrialNet group did HLA typing and found that she had a protective HLA type, not an HLA type that is associated with Type 1 diabetes. So they took those patients who had protective HLA alleles and did genetic testing. She was found to have a particular single amino acid mutation in the ABCC8 gene. She was a heterozygous for a CA3L67 C-to-T mutation. This mutation has not been described very often. It's described one other time in a patient who had transient neonatal diabetes that then recurred when he was a teenager. The ABCC8 mutations are associated with either permanent or transient neonatal diabetes. They're autosomal dominant in inheritance, but all of the autosomal dominantly inherited problems, because it only requires that one gene be mutated, are also more susceptible to de novo mutations. So this patient appears to have a de novo mutation because her parents don't have diabetes. Her brother was tested. He does not have the same problem, and there's no other family history.

So what happened to this patient? It's well known that persons with ABCC8 mutations may respond to sulfonylureas. She was on an insulin pump, and the question is where do you go from here? She was transferred from the insulin pump with escalating doses of sulfonylureas as her insulin doses weaned off over a couple of weeks. And she has been treated with sulfonylureas since then, which is about the last four years. So very good outcome for this patient thanks to an investigative work on the part of the TrialNet group, and then physicians at the University of Washington. They're a little bit tricky to treat, however. These patients may require higher doses of sulfonylureas. They're difficult to find the right dose and the right regimen for them. So when I last saw her, her comment was "Why don't I just go back on an insulin pump? It was easier in some ways." We had her taking two types of sulfonylurea. However, not taking insulin is still not taking insulin, so she was pretty happy about that.

Sina Jasim, MD, MPH: Yeah, this is a significant change, to go from insulin to oral agents. So Dr. McGill, is it fair to say patients suspected of having Type 1 diabetes but with atypical clinical characteristics, so presentation like negative antibodies, low insulin requirement, or persistence of C-peptide, should undergo genetic testing for monogenic diabetes? In other words, what are the patients that make us suspect these are not classic Type 1 or Type 2 and they should go under testing for monogenic diabetes?

Janet B. McGill, MD, MA, FACE, FACP: That's a very good question. Our threshold for doing genetic testing has changed over the last few years. And it starts with the characteristics that you mentioned, patients who are antibody negative, C-peptide positive, though in some cases the C-peptide is very, very low. And this patient was one of those where the C-peptide was very low. Nonetheless, she was able to come off insulin and be managed with sulfonylurea. ABCC8 is a very minor, very low percent cause of MODY. It is one of the MODY types, but any antibody-negative patient, maybe persistence of C-peptide, maybe takes less insulin than would be expected, I would consider doing monogenic testing.

The other group that we need to think about doing monogenic testing in are patients with other disease manifestations. For example, the most common type of MODY, MODY 3, which is HNF1 alpha, they may have liver cysts. So when you see a young patient who has cystic liver disease or cystic kidney disease, that patient should undergo monogenic testing for diabetes since the gene defect is not specific to beta cells, but does involve other organs in the body.

Sina Jasim, MD, MPH: And this is really relevant, and I think we have a visual vignette that was also published under that category. Dr. McGill, combining these cases together and all we've talked about, what are additional important teaching points or clinical relevance that you would like to highlight?

Janet B. McGill, MD, MA, FACE, FACP: I think the answer to that is expand our knowledge base, expand our diagnostic acumen. Don't be afraid to look at that patient who's had diabetes for 10 or 15 years through sort of a new lens when you see other disease manifestations because it could make a difference in their treatment, it could make a difference in their family's risk, and it could make a difference in the way that you follow that patient. And I have done genetic testing that has come back negative. I have more positive tests than negative tests, but I have had a couple of negative tests, and I still think it was absolutely the right thing to do in these cases.

Sina Jasim, MD, MPH: Absolutely. So certain criteria make you have a lower threshold to test because now we're seeing more and more of these cases. And the availability of this testing, of course, it's helpful. Are there any additional thoughts that you'd like to share regarding those cases or the field in general?

Janet B. McGill, MD, MA, FACE, FACP: So I would like to remind the listeners that genetic testing is not actually difficult because you order panels. So you would order an entire panel for MODY defects or for neonatal diabetes or for... There's a lipodystrophy panel, for example. So it's not necessary to know in advance the gene defect. Sometimes we have suspicions, but it's not necessary that you know it exactly. The genetic testing is done on a saliva sample, so it's easy to acquire. There are forms to fill out and then it is sent in. It can be done in an office setting. Once you identify the genetic testing facility that you'd like to use, it typically comes as a kit. They'll be happy to provide it. And then you simply select the gene panel that fits this patient's problem the best.

Sina Jasim, MD, MPH: Sounds great. Dr. McGill, I want to thank you very much for joining us today to share your expertise in these cases in the field. To learn more about those cases or other related cases, or to submit your own interesting case or visual vignette, please visit www.AACEclinicalcasereport.com. This is Sina Jasim, and thank you for listening.

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